SIGNAL TRANSDUCTION PATHWAYS LINK SIGNAL RECEPTION WITH CELLULAR

RESPONSE

Cells communicate by generating, transmitting and receiving chemical signals

Cascade of Molecular Interactions

Relay molecules – often proteins, transmit the signal from the receptor to the final cellular response

Message is sent by phosphorylating and dephosphorylating protiens (results in shape changes)

Phosphorylation done by kinases – activating

Dephosphorylation done by phophatases - deactivating

Phosphorylation Cascade

Cascade of Molecular Interactions

Second messengers – water soluble molecules and / or ions can be involved in the transduction of messages from signal to cellular response

Second messengers are often essential to the function of cascade

Small / water soluble = rapid diffusion thru cells

Illustrative Example: cyclic AMP (cAMP) as a second messenger

First messenger (i.e. epinephrine) triggers G-protein receptors

Receptor protein triggers adenylyl cyclase which catalyses Rapid synthesis of many cAMP molecules from Atp molecules

High camp concentrations are quickly reduced by phosphodiesterase (which converts cAMP to AMP)

Repeated stimulation by first messenger is required to maintain high concentrations of camp in cytoplasm

High levels of cAMP trigger the activation of kinases that eventually bring about the cellular response

Illustrative Example: calcium (Ca2+) ions and inositol triphosphate (IP3 ) as a second messengers

Calcium is more widely used than cAMP as a second messenger

Ca2+ used with G-protein receptors and tyrosine kinase pathways

Good secondary messenger because the concentration of Ca2+ is usually very low (it is actively pumped out of cytoplasm either into extra cellular fluid, into ER, or into mitochondria)

IP3 is another secondary messenger which can stimulate the release of Ca2+

Cellular Response

Nuclear Responses Many signaling

pathways regulate protein synthesis by turning a gene on or off

Phosphorylation cascades can end by activating or inactivating a transcription factor

Cellular Response

Cytoplasmic Response Signaling pathways

regulate the activity of proteins found in the cytosol

For example: Epinephrine stimulating the breakdown of glycogen via signal transduction

Specificity of cell signaling

The particular protiens a cell possesses determine what signaling molecules it responds to and the nature of the response.

4 different cells each respond to the same signaling molecule in a different way

Signaling

molecule

Receptor

Relay molecule

s

Response 1

Cell A. Pathway leads to a single response.

Response 2 Response 3

Cell B. Pathway branches, leading to two responses.

Response 4 Response 5

Activation or inhibition

Cell C. Cross-talk occurs between two pathways.

Cell D. Different receptor leads to a different response.

Apoptosis integrates multiple cell-signaling pathways

Apoptosis – programmed cell death; cellular agents chop up the DNA, fragment the organelles & other cellular components; the cell shrinks and becomes lobed (blebbing); cell parts are packaged up in vesicles that are engulfed & digested by specialized scavenger cells

Apoptosis controlled by signal transduction pathways

Study of soil worm (Caenorhabditis elegan) reveal that there are cell death genes and cell death proteins (Ced -3 and Ced-4) that are always present in the cell in the inactive form.

These proteins can be “turned on or off” by signal transduction pathways that

Ced-9 protein

(active) inhibits

Ced-4 activity

Mitochondrion

Receptor

for death-

signaling

molecule

Ced-4

Ced-3

Inactive proteins

(a) No death signal

Ced-9

(inactive)

Cell

forms

blebs

Death-

signaling

molecule

Other

proteases

Active

Ced-4

Active

Ced-3

Nucleases

Activation

cascade

(b) Death signal

Apoptosis

Caspases are the main proteases (enzymes that cut up proteins) that carry out apoptosis

Apoptosis can be triggered by: An extracellular death-signaling ligand DNA damage in the nucleus Protein misfolding in the endoplasmic reticulum

Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers

Apoptosis evolved early in animal evolution and is essential for the

development and maintenance of all animals